Autosomal Dominant Polycystic kidney Disease (ADPKD) is the most common life threatening hereditary disease in the USA and it accounts for about 5-10% of end-stage renal failure requiring dialysis and renal transplantation. Apoptosis in cells lining the cysts as well as in non-cystic is a characteristic feature of animal models of ADPKD as well as human ADPKD. Apoptosis is thought to play a role in both cyst formation and the loss of normal tubules and subsequent renal failure. The central component of the apoptosis machinery is a novel family of cysteine proteases called caspases. Cell permeable caspase inhibitors have been widely used in animal studies in vivo to dramatically alter a variety of pathological processes. The effect of caspase inhibition on apoptosis, proliferation, cyst formation and renal failure in ADPKD forms the basis of this grant proposal. The overall hypothesis presented in this grant proposes that dysregulation of the balance between pro and anti-apoptotic Bcl-2 family proteins leads to activation of the "initiator" caspases 8 or 9 and the "executioner" caspase-3. Further, it is proposed that apoptosis precedes proliferation leading to cyst formation and that apoptotic loss of non-cystic renal tubules leads to renal failure. Complementary studies will be performed in Han:SPRD rats and Pkd2 mutant mice, which closely resemble human ADPKD. In Specific Aim #1 we shall describe the time course and localization of apoptosis and proliferation. Specific Aim #2 focuses on in vivo studies to determine whether caspase inhibitors will attenuate apoptosis, proliferation, cyst formation and renal failure. Caspase activity, protein and gene expression will be measured. Functional (serum urea and creatinine) and morphological (renal cyst size, proliferation and apoptosis) correlates will be documented. In Specific Aim #3,, the relationship between Bcl-2 gene family protein expression and caspase-3 activity will determined. The potential relevance of these studies to clinical ADPKD is substantial and the results should provide leads to altering the course of ADPKD. This is particularly true because of the current availability of cell permeable, non toxic caspase antagonists that are active in vivo.